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Kruppel-like factor 4 (KLF4) is a transcription factor regulating cell growth and differentiation. In normal tissues, Kruppel-like factor 4 (KLF4) is typically expressed in post-mitotic epithelial cells and functions in epithelial cell differentiation. However, in the premalignant dysplastic lesions and invasive cancers of specific human tumor types such as skin cancer and breast cancer, KLF4 mRNA and protein are upregulated in proliferating cells. When KLF4 misexpressed in the basal keratinocytes of mouse skin, KLF4 can rapidly induce neoplastic progression to squamous cell carcinoma-like lesions. Consistent with its preferential expression in post-mitotic cells in vivo, KLF4 is likewise induced upon growth-arrest in vitro. Currently, the mechanisms leading to induction of KLF4 upon growth arrest in normal cells or its upregulation in cancer cells remain incompletely understood. In the first study (Chapter 2), we addressed the mechanisms leading to the distinct expression pattern of KLF4 during the proliferation/differentiation switch. We recapitulated the proliferation-dependent regulation of KLF4 using an epithelial cell model, RK3E cells. In these cells, the endogenous Klf4 RNA and protein was low in proliferating cells but high in post-confluent cells that form an epithelial sheet, with up regulation of cell cycle inhibitors such as p21Waf1/Cip1 and p27Kip1. We mapped potential regulatory elements by inserting fragments of KLF4 cDNA into the 3’ UTR of a firefly luciferase reporter. By measuring the luciferase mRNA and protein levels, we identified a cell-cycle-dependent translational-control element (TCE) in KLF4. This element mediates translational inhibition in proliferating normal epithelial cells, but not in cancer cells where endogenous KLF4 expression is higher. To further investigate the TCE, we used primary human mammary epithelial cells (HMECs), immortalized MCF10A cells, and malignant tumor-derived cell lines as models. We showed that in proliferating HMECs, as in rat RK3E cells, the TCE mediated a low translational efficiency. In contrast, in MCF10A cells and malignant tumor cells where endogenous KLF4 is more highly expressed, the TCE was not inhibitory. This altered function of the TCE was also observed during the epithelial-mesenchymal transition (EMT) of mammary epithelial cells in vitro. Overall, a role for microRNAs (miRs) in TCE function was suggested by the effects of Dicer1 (DCR1) knockdown on TCE function and on expression of endogenous KLF4. Further studies showed that miR-206, and miR-344-1 was responsible for altering the function of the TCE. In epithelial cells, miR-206 promotes KLF4 translation; however, in mesenchymal-like cells, it repressed the translation of KLF4. Furthermore, we found that KLF4 can regulate miR-206 expression in both epithelial and mesenchymal-like cells. Taken together, these results identify a KLF4 posttranscriptional control mechanism that is altered during tumor progression and EMT. In the second study (Chapter 3), we further characterized the roles of this KLF4-miR-206 regulatory axis in EMT and their roles in breast cancer progression. We showed that KLF4 is an important regulator of breast cancer cell migration in vitro and tumorigenicity in vivo . The KLF4-miR-206 regulatory axis is conserved across normal mammary epithelial cells and mesenchymal-like breast cancer cells. The effect of miR-206 on KLF4 translation was switched from promotion to suppression during TGF-β-mediated EMT of MCF10A cells. This distinct translational control of miR-206 between epithelial and mesenchymal-like cells were conserved for another miR-206 target mRNA, Cx43. In addition, KLF4-miR-206 axis and ZEB1, an important EMT activator, revealed an autoregulatory feedback loop in both normal mammary epithelial cells and breast cancer cells. This ZEB1/KLF4-miR-206 autoregulatory axis potentially induces normal mammary epithelial to mesenchymal-like breast cancer cell transition. Our studies indicate that miR-206 can act as tumor suppressor by promoting Cx43 protein levels and suppressing cell migration in normal mammary epithelial cells. Alternatively, miR-206 can act as an oncogene by suppressing Cx43 protein expression and promoting cell migration and invasion in mesenchymal-like breast cancer cell. In summary, the KLF4-miR-206 regulatory axis may contribute to EMT and breast cancer tumorigenesis. Targeting this pathway may provide new avenues for breast cancer therapy.